DESCRIPTION: (Adapted from the application) The applicant is strongly committed to an academic career in neurology and ultimately hopes to divide his time between clinical practice and basic science research into mechanisms of neurodegeneration in diseases of the aging brain. His career plan is to use a multi-disciplinary approach to study cellular mechanisms of selective neurodegeneration. To achieve these goals, he will greatly benefit from the protected period provided by a KO1 award, during which he can learn certain new techniques and take relevant course work, while being fully immersed in research. He has chosen Dr. John Weiss as mentor because of his overlapping research interest and expertise and leadership in the field of selective neurodegeneration. He is confident that the combination of intensive research training under his guidance, and the outstanding research environment at UCI (with experts available for technical assistance on any problem) will fully prepare him for launching an independent research career. A critical feature of neuronal damage associated with diseases of the aging brain (including Alzheimer's disease; AD) is a highly selective pattern of neuronal loss. A factor that may contribute to selective neurodegeneration in these diseases is expression of AMPA/kainate type glutamate receptors gating channels that are permeable to Ca2+. A growing body of evidence suggests another possible factor: endogenous Zn2+. Vesicular Zn2+ can be released from pre-synaptic glutamatergic terminals and can translocate into the cytoplasm of postsynaptic neurons where it may trigger degeneration. Prior studies from the lab indicate that Zn2+ permeates Ca2+ permeable AMPA/kainate channels with particular rapidity. This proposal follows from the hypothesis that Zn2+ permeation through these channels contributes to aging related neurodegeneration. Initial experiments will employ histologic, fluorescent imaging and whole cell recording techniques to investigate cellular and subcellular sites of expression of these channels and to characterize their permeability to Zn2+. Subsequent experiments will examine certain consequences of such Zn2+ permeation of relevance to neurodegeneration. Specifically, effects of Zn2+ entry on intracellular Ca2+ handling or influx on oxididative metabolism and mitochondrial function, and interactions between Zn2+ mediated and B-amyloid mediated injury will be assessed. It is hoped that these studies will increase understanding of cell injury mechanisms in diseases of aging and suggest new therapies.